Anomeric O-Functionalization of Carbohydrates for Chemical Conjugation to Vaccine Constructs.

Carbohydrates mediate a wide range of biological interactions, and understanding these processes benefits the development of new therapeutics. Isolating sufficient quantities of glycoconjugates from biological samples remains a significant challenge. With advances in chemical and enzymatic carbohydrate synthesis, the availability of complex carbohydrates is increasing and developing methods for stereoselective conjugation these polar head groups to proteins and lipids is critically important for pharmaceutical applications. The aim of this review is to provide an overview of commonly employed strategies for installing a functionalized linker at the anomeric position as well as examples of further transformations that have successfully led to glycoconjugation to vaccine constructs for biological evaluation as carbohydrate-based therapeutics

Oxetanes: Recent Advances in Synthesis, Reactivity and Medicinal Chemistry

The 4-membered oxetane ring has been increasingly exploited for its behaviors, i.e. influence on physicochemical properties as a stable motif in medicinal chemistry, and propensity to undergo ring opening reactions as a synthetic intermediate. These applications have driven numerous studies into the synthesis of new oxetane derivatives. This review takes an overview of the literature for the synthesis of oxetane derivatives, concentrating on advances in the last 5 years up to the end of 2015. These methods are clustered by strategy for preparation of the ring (Sections 3 and 4), and further derivatisation of preformed oxetane-containing building blocks (Sections 5-7). Examples of the use of oxetanes in medicinal chemistry are reported, including a collation of oxetane derivatives appearing in recent patents for medicinal chemistry applications. Finally examples of oxetane derivatives in ring opening and ring expansion reactions are described

Lithiation of 4-membered heterocycles as useful strategy for the preparation of new molecular scaffolds: addressing the regioselectivity in azetidines and thietanes

Four-membered heterocycles (4-MH) with one or two heteroatoms are of great importance in medicinal chemistry and synthetic organic chemistry. This kind of scaffolds show peculiar structural features, related to the ring “puckering”, and biological properties. Our recent research efforts have been focused on the stereoselective synthesis and functionalization of some 4-MH such as azetidines, thietanes and oxazetidines

C-H & C-O Functionalization by Silicon-Heteroatom Interelement Linkage

La química sintètica és gairebé inimaginable sense tres elements principals del grup, a saber, boro, silici i estany. Quan s'uneixen a un àtom de carboni de qualsevol hibridació, aquests grups funcionals serveixen de linchpins excepcionalment versàtils en síntesi, transformant-se selectivament en una enorme amplitud d'enllaços C-C i C-X, per tant, descobrir nous mètodes per forjar el valor afegit C-Si, Els enllaços C-B i C-Sn sempre tenen una gran demanda. D'acord amb l'interès de la investigació en el grup de Martín per activar enllaços o molècules inerts, aquesta tesi doctoral se centra en el desenvolupament de noves tècniques per fer ús de l'enllaç d'interrelació de silici-heteroatoma per funcionalitzar l'enllaç C-O i C-H inerts mitjançant una catàlisi de níquel o sistema lliure de transició de metalls. Hem desenvolupat tres nous mètodes per a la funcionalització d’enllaços C-O i C-H inerts mitjançant l’ús d’enllaços d’interrelació basats en silici. Totes les transformacions anteriors presenten un excel·lent perfil de quimioselectivitat en condicions suaus. Es duen a terme estudis i debats sobre mecanismes previs per entendre com i per què van continuar aquestes reaccions. Les transformacions realitzades contribueixen a la comprensió de l’ús més prolífic d’enllaços químics inerts en els compostos de valor afegit de síntesi. Creiem que aquests protocols contribuirienLa química sintética es casi inimaginable sin tres elementos principales del grupo, a saber, boro, silicio y estaño. Cuando se unen a un átomo de carbono de cualquier hibridación, estos grupos funcionales sirven como linchpins excepcionalmente versátiles en síntesis, transformándose selectivamente en una enorme variedad de enlaces C-C y C-X, por lo tanto, descubren nuevos métodos para forjar el valor agregado C-Si, Los bonos C-B y C-Sn siempre tienen una gran demanda. En línea con el interés de la investigación en el grupo de Martín de la activación de enlaces o moléculas inertes, esta tesis doctoral se centra en el desarrollo de nuevas técnicas para hacer uso del enlace de interelemento de silicio-heteroátomo para funcionalizar el enlace inerte C-O & C-H a través de catálisis de níquel o sistema sin transición de metal. Hemos desarrollado tres nuevos métodos para la funcionalización de enlaces inertes C-O y C-H mediante el uso de enlaces de interelemento basados ​​en silicio. Todas las transformaciones anteriores muestran un excelente perfil de quimioselectividad en condiciones suaves. Se realizan estudios y debates mecanicistas preliminares para comprender cómo y por qué se produjeron estas reacciones. Las transformaciones realizadas contribuyen a la comprensión del uso más prolífico de enlaces químicos inertes a los compuestos de valor agregado de síntesis.Synthetic chemistry is almost unimaginable without three main group elements, namely, boron, silicon, and tin. When attached to a carbon atom of any hybridization, these functional groups serve as exceptionally versatile linchpins in synthesis, selectively transforming into an enormous breadth of C-C and C-X bonds, thus, discover new methods to forge value added C-Si, C-B and C-Sn bonds are always in highly demand. In line with the research interest in Martín’s group of activating inert bonds or molecules, this doctoral thesis focuses on the development of novel techniques to make use of silicon-heteroatom interelement linkage to functionalize inert C-O & C-H bond via either nickel catalysis or transition metal free system. We have developed three new methods towards the functionalization of inert C-O & C-H bonds by using silicon-based interelement linkages. All the above transformations display excellent chemoselectivity profile under mild conditions. Preliminary mechanistic studies and discusses are carried out to understand how and why these reactions proceeded. The transformations realized contribute to the understanding of more prolific use of inert chemical bonds to the synthesis value added compounds. We believe these protocols would definitely contribute to a systematic utilization of silicon-heteroatom reagent in the arena of inert chemical bond functionalization

Borane-ctalyzed stereoselective C–H insertion, cyclopropanation, and ring-opening reactions

Lewis acidic boranes have been shown to be effective metal-free catalysts for highly selective reactions of donor-acceptor diazo compounds to a range of substrates. The reactions of α-aryl α-diazoesters with nitrogen heterocycles indole or pyrrole selectively generate C3 and C2 C–H insertion products, respectively, in good to excellent yields even when using unprotected indoles. Alternatively, benzofuran, indene, and alkene substrates give exclusively cyclopropanated products with α-aryl α-diazoesters, whereas the reactions with furans lead to ring-opening. Comprehensive theoretical calculations have been used to explain the differing reactivities and high selectivities of these reactions. Overall, this work demonstrates the selective metal-free catalytic reactions of α-aryl α-diazoesters with (hetero)cycles and alkenes. This simple, mild reaction protocol represents an alternative to the commonly used precious metal systems and may provide future applications in the generation of biologically active compounds

Photografted methacrylate-based monolithic columns coated with cellulose tris(3,5-dimethylphenylcarbamate) for chiral separation in CEC

A chiral capillary monolithic column for enantiomer separation in capillary electrochromatography was prepared by coating cellulose tris(3,5-dimethylphenylcarbamate) on porous glycidyl methacrylate-co-ethylene dimethacrylate monolith in capillary format grafted with chains of [2(methacryloyloxy)ethyl] trimethylammonium chloride. The surface modification of the monolith by the photografting of [2(methacryloyloxy)ethyl] trimethylammonium chloride monomer as well as the coating conditions of cellulose tris(3,5-dimethylphenylcarbamate) onto the grafted monolithic scaffold were optimized to obtain a stable and reproducible chiral stationary phase for capillary electrochromatography. The effect of organic modifier (acetonitrile) in aqueous mobile phase for the enantiomer separation by capillary electrochromatography was also investigated. Several pairs of enantiomers including acidic, neutral, and basic analytes were tested and most of them were partially or completely resolved under aqueous mobile phases. The prepared monolithic chiral stationary phases exhibited a good stability, repeatability, and column-to-column reproducibility, with relative standard deviations below 11% in the studied electrochromatographic parameters.Fil: Echevarria, Romina Noel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas; ArgentinaFil: Carrasco Correa, Enrique Javier. Universidad de Valencia; EspañaFil: Keunchkarian, Sonia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas; ArgentinaFil: Reta, Mario Roberto. Universidad Nacional de La Plata. Facultad de Ciencias Exactas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Herrero Martinez, José Manuel. Universidad de Valencia; Españ

Stereoselective alkoxycarbonylation of unactivated C(sp^3)–H bonds with alkyl chloroformates via Pd(II)/Pd(IV) catalysis

Several examples on Pd-catalysed carbonylation of methyl C(sp^3)–H bonds with gaseous CO via Pd(II)/Pd(0) catalysis have been reported. However, methylene C(sp^3)–H carbonylation remains a great challenge, largely due to the lack of reactivity of C–H bonds and the difficulty in CO migratory insertion. Herein, we report the stereoselective alkoxycarbonylation of both methyl and methylene C(sp^3)–H bonds with alkyl chloroformates through a Pd(II)/Pd(IV) catalytic cycle. A broad range of aliphatic carboxamides and alkyl chloroformates are compatible with this protocol. In addition, this process is scalable and the directing group could be easily removed under mild conditions with complete retention of configuration

Recent advances in the total synthesis of agelastatins

Agelastatins represent an important family of marine alkaloids in terms of both exceptional biological activity and intriguing chemical structure. In this article, the isolation and biological activity of agelastatins are reviewed, and proposed biosynthetic pathways are summarized. The main focus is given to comparative evaluation of recent total syntheses, mainly of agelastatin A. To date, this has been accomplished by 11 research groups. Their synthetic routes are analyzed and summarized, with a view to furnishing the reader with insight into different strategic design approaches to assembly of a densely functionalized and compact structure